This invention relates to the use of a pharmaceutical composition containing essential fatty acid ethyl esters originating from fish oils, in particular as a high concentration mixture of ethyl esters of (20:5ω 3) eicosapentaenoic acid (EPA) and (22:6ω 3) docosahexaenoic acid (DHA) for the treatment and/or inhibition of depression in patients with coronary artery disease.
It is known that certain essential fatty acids contained in fish oil have a therapeutic effect in the prevention and treatment of cardiovascular disorders, such as in the treatment of hypertension, thrombosis, hypercholesterolemia, arteriosclerosis, cerebral infarction, prevention of sudden death in post myocardial infarction patients, improvement of endothelial function and hyperlipedemias. See, for example, U.S. Pat. Nos. 5,502,077; 5,656,667, and 5,698,594. The prevention of cardiovascular events, especially of mortality in patients who have survived the hospitalization phase of acute myocardial infarction (AMI), is described in the international patent application no. WO 00/48592.
The foregoing prior art in particular provides knowledge about the utility of fatty acids belonging to the ω-3 family, more specifically (20:5ω 3) eicosapentaenoic acid (EPA) and (22:6ω 3) docosahexaenoic acid (DHA), in treating the aforementioned disorders.
The fatty acid EPA, being a precursor of PGI3 and TxA3, exerts a platelet aggregation preventing effect and an antithombotic effect that can be ascribed to inhibition of cyclooxygenase (similar effect to that of aspirin) and/or to competition with arachidonic acid for this enzyme, with consequent reduction in the synthesis of PGE2 and TxA2, which are well known platelet aggregating agents.
On the other hand the fatty acid DHA is the most important component of cerebral lipids in man and furthermore, being a structural component of the platelet cell, it intervenes indirectly in increasing platelet fluidity, thus playing an important role in antithombotic activity.
International patent application WO 89/11521, the disclosure of which is incorporated herein by reference, describes in particular an industrial process for extracting mixtures having a high content of poly-unsaturated acids, including EPA and DHA and their ethyl esters, from animal and/or vegetable oils. Mixtures of fatty acids, especially EPA/DHA, obtained according to WO 89/11521, are reported to be particularly useful in the treatment of cardiovascular diseases.
However, current methods of treatment used in human therapy have been shown to be insufficient in patients with coronary artery disease.
Recently new risk factors for coronary artery disease have been identified, among them depression. Major depressive disorders, as well as depression symptoms, are associated with higher rates of cardiovascular morbidity and mortality. Moreover, once the ischemic heart disease is established, the risk of suffering a fatal cardiac event is increased. Severe ventricular arrhythmias resulting in sudden cardiac death appear to be the leading cause of mortality in patients with depression. In addition, patients with anxiety and depressive disorders have been shown to have reduced heart rate variability. This finding may have important prognostic implications because low heart rate variability is a powerful predictor of sudden cardiac death.
There is substantial evidence that major depression is associated with alterations in omega-3 acids status. A significant depletion of red cell membrane omega-3 fatty acids has been reported in major depression. Another study reported a negative correlation between severity of depression and both red blood cell membrane content of omega-3 fatty acids and dietary intake of these polyunsaturated fatty acids. Supplementation with EPA and DHA is known to increase the content of these unsaturated fatty acids in erythrocyte membranes. Studies in post-myocardial infarct patients have demonstrated that supplementation with DHA and EPA improves heart rate variability.
However, currently there are no safe and effective treatments known to inhibit depression in patients with cardiovascular disease and hardly any other treatments of depression in patients with cardiovascular disease. One study with sertraline showed beneficial effects in post-myocardial patients with concomitant depression. It is well known that patients with cardiovascular diseases and depression are at a substantially increased risk of cardiovascular events and death.
Therefore, there is still a substantial need for improved and effective treatment and/or inhibition with drugs, in particular for preventing these recurrences in patients suffering from both cardiovascular diseases and depression, and for the effective treatment of depression in these patients.